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PMCOL 200 > Final Exam > Flashcards

Final Exam Flashcards

1
Q

“Life” cycle of viral replication

A

absorption, penetration, replication, release

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2
Q

DNA viruses

A
  • most enter the host cell nucleus, where the viral DNA is integrated into the host genome and transcribed into mRNA by host DNA-dependent RNA polymerase; mRNA is translated into virus-specific proteins
  • Poxviruses are an exception; they carry their own DNA-dependent RNA polymerase and replicate in the host cell cytoplasm
  • viral genome replication requires DNA-dependent DNA polymerase
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3
Q

Double stranded RNA viruses require

A

RNA-dependent RNA polymerases

- so virus must make itself (RNA -> mRNA)

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4
Q

The viral RNA-dependent RNA polymerase acts both as a …

A

transcriptase to transcribe mRNA and replicase to replicate the viral genome

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5
Q

This copies viral RNA into DNA (RNA-dependent DNA polymerase

A

reverse transcriptase
- the resulting viral DNA is integrated into the host DNA (then transcribed into mRNA and translated into protein by host enzymes)

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6
Q

Antiviral drugs can exert actions at several stages of viral replication including:

A
  • viral entry
  • nucleic acid synthesis
  • protein synthesis
  • viral packaging
  • virion release
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7
Q

Virustatic

A

only active against replicating viruses and do not affect latent viruses
(antivirals!)

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8
Q

Acyclovir

A
  • Anti-Herpes drug
  • nucleoside (guanine) analogue (fake DNA binding block) which viruses incorporate into their genomes during replication
  • lacks a hydroxyl group important for forming the backbone of the DNA molecule (DNA chain termination)
  • *viral life cycle halted because newly synthesized DNA is inactive**
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9
Q

Thymidine kinase

A

acyclovir must be phosphorylated to acyclovir-triphosphate to be incorporated into viral DNA as a terminal substrate
- the first phosphate is added by TK, which has an affinity or acyclovir that is about 200 times that of the mammalian enzyme (specificity; does not affect human genome)

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10
Q

Acyclovir resistance in herpes simplex virus can result from:

A
  • impaired production of viral thymidine kinase
  • altered thymidine kinase substrate specificity (ex: phosphorylation of thymidine but not acyclovir)
  • altered viral DNA polymerase
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11
Q

Lentivirus

A
  • a family of retroviruses that lead to chronic persistent infection with gradual onset of clinical symptoms
  • HIV
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12
Q

HIV infects these human immune cells

A
  • CD4+ T cells
  • when they decline below a critical level, cell mediated immunity is lost and the body becomes susceptible to opportunistic infections (AIDS)
  • replication constant following infection; absence of treatment = no true period of viral latency following infection
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13
Q

HAART

A
  • HIV
  • involves drug combinations that can slow or reverse the increases in viral RNA load that normally accompany progression of disease
  • antiviral HIV drugs target fusion, transcription, integration into host genome, and virion release
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14
Q

Maraviroc (HIV)

A

CCR5 receptor antagonist (interferes with HIV binding to T cell)

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15
Q

Nucleoside Reverse Transcriptase Inhibitors (NRTI) (HIV)

A
  • HIV reverse transcriptase enzyme synthesizes DNA from HIV RNA using nucleosides in the host T-cell (RNA dependent DNA polymerase)
  • small molecule drugs that are similar to the host cell nucleosides, and are incorporated into new HIV DNA chain as if they were endogenous nucleosides
  • because NRTIs lack a 3’ OH group on the ribose ring, attachment of the next nucleoside is impossible (chain termination)
  • mammalian RNA and DNA polymerases are sufficiently distinct to permit a selective inhibition of viral reverse transcriptase
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16
Q

Integrase Strand Transfer Inhibitors (INSTs) (HIV)

A
  • integrase is a viral enzyme that inserts viral genome into the DNA of the host cell
  • integrase inhibitors block the action of integrase to inhibit HIV proliferation
  • Raltegravir
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17
Q

Protease Inhibitors (HIV)

A
  • assembly of infectious HIV virion is dependent on aspartate proteases; this viral enzyme cleaves precursor proteins to form the final structural proteins of the mature virion core (inhibits last step before release)
  • HIV protease inhibitors are designer drugs based on molecular characterization of the active site of the viral enzyme
  • usually used in combination with reverse transcriptase inhibitors
  • inhibitors bind to active site on aspartate proteases so proteins are no longer cleaved into that final mature form so inhibits ability of virion particle to mature and to be virulent
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18
Q

Amantadine

A
  • Influenza
  • inhibit an early step in replication (viral uncoating) of the influenza A virus
  • M2 protein functions as a proton ion channel required at the onset of infection to permit acidification of the virus core, which in turn activates viral RNA transcriptase
  • blocks proton (H+) transfer through M2, thus blocking acidification and the initiation of viral transcription
  • prophylactic against A not B; can reduce duration of symptoms if given within 48 hours after contact
  • BUT many resistant influenza A virus mutants (H3N2)
  • vaccination is more cost-effective
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19
Q

This is an alternative in high-risk patients if the influenza vaccine cannot be administered or may be ineffective (immunocompromised)

A

seasonal prophylaxis using antivirals

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20
Q

Zanamivir

A
  • neuraminidase inhibitors (influenza A and B)
  • these enzymes cleave sialic acid residues from viral proteins that enables virus to be released from the host cell
  • by interfering with these actions, neuraminidase inhibitors impede viral spread
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21
Q

The leading cause of death in Canada (1 in 4 deaths)

A

Cancer (over 100 types)

- Not really very good drugs to treat cancer

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22
Q

Metastasis

A

spreading to other parts of body

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23
Q

Radon

A

natural occurring gas in our soil that can be released overtime; Ab has some of the highest levels of radon in the soil in the world; poorly ventilated basement this can be an issue; second most cause of cancer after smoking

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24
Q

Cancer arises when this happens

A

when genes that regulate cell growth are mutated
- mutations occur and cells can detect it and initiates appropriate response = apoptosis
BUT in specific types of mutations, particularly in genes that regulate cell growth = mutation override cell’s ability to control or to regulate cell division so cell continues dividing despite mistakes made during duplication of DNA = unchecked/uncontrolled cell division

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25
Q

Cell cycle

A
  • G1 phase: checkpoint to ensure cell ready for DNA synthesis
  • S phase: DNA synthesis
  • G2 phase: checkpoint to ensure cell ready for mitosis
  • M phase: mitotic phase (cell divides into two daughter cells)
  • G0 phase: quiescent state
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26
Q

Tumor suppressor genes (and the proteins ithey encode)

A
  • repress cell cycle or promote apoptosis
    > inhibit cell division
    > initiate apoptosis following irreversible DNA damage
    > DNA repair proteins (BRCA)
  • p53 is tumor suppressor protein that regulates cell cycle; mutated in 50% of all tumors
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27
Q

Gene important in repairing mutations in DNA sequences so it can restore normal functioning of cell =

A

BRCA gene

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28
Q

Proto-oncogenes

A

normal genes involved in cell growth and proliferation or inhibition of apoptosis
- mutations can increase expression (oncogene)
- mutations can be:
> point: small scale deletions or insertions which affect its expression
> chromosomal translocation: when two separate chromosomal regions become abnormally fused

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29
Q

Philadelphia chromosome

A

specific genetic abnormality in chromosome 22 found in leukemia cancer cells (abnormal translocation of chromosome 9 and 22)

  • broken end of 22 contains the BCR gene which fuses with a fragment of chromosome 9 that contains the ABL1 gene (tyrosine kinase protein - important at regulating cell growth)
  • fusion creates a new gene = BCR-ABL
  • leads to unregulated expression of protein tyrosine kinase activity leading to unregulated cell cycle and cell division
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30
Q

Cancer Therapy

A
  • 1/3 cured with local treatment strategies such as surgery or radiotherapy
  • remaining cases = systemic approach with anti-cancer drugs is required due to metastasis
  • anticancer drugs alone cure less than 10% of all cancer patients when tumor is diagnosed at advanced stage (usually given in combination with surgery and radiation)
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31
Q

Tamoxifen

A

anti-cancer drug that is cytotoxic at any point in the cell cycle

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32
Q

T or F. Few categories of medication have a narrower therapeutic index and greater potential for causing harmful effects than anti-cancer drugs

A

T

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33
Q

Four bases form DNA two (?) and two (?)

A

pyrimidines (thymine and cytosine)
and purines (guanine and adenine)
** RNA incorporates uracil instead of thymine **

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34
Q

Pyrimidine analogues

A
  • compete with normal pyrimidines precursors for the enzyme thymidylate synthase (TS)
  • TS required for the conversion of dUMP to dTMP (thymine + deoxyribose sugar)
  • i.e. 5-fluorouracil (5-FU)
  • inactive in its parent form and requires activation to active metabolite FdUMP
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35
Q

5-FU

A

pyrimidine analogues; prodrug!

needs to be metabolized into an active metabolite: FdUMP = inhibits function of thymidylate synthase

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36
Q

Thymidylate Synthase (TS)

A
  • important for maturation of pyrimidine bases (C or T)
  • involved in conversion of precursor molecule dUMP into mature base thymine for ex
  • thymine monophosphate to be converted into thymine triphosphate where it can then be incorporated into a growing DNA chain (deoxyribose sugar important for growing DNA chain)
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37
Q

Purine analogues

A
  • 6-mercaptopurine inhibits purine nucleotide biosynthesis and metabolism by inhibiting an enzyme called phosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase)
  • rate limiting factor for purine synthesis (PRPP amidotransferase), so drugs that inhibit that enzyme alters the synthesis and function of RNA and DNA

bc no building blocks available to make DNA, then this interferes with cell division

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38
Q

Alkylating agents

A

highly reactive compounds which covalently link to chemical groups (phosphates, amines, sulfhydryl and hydroxyl groups) commonly found in nucleic acids
- lead to cross-linking between strands of DNA and strand breakage

in order to replicate DNA normally , need to separate strands of DNA in order to let enzyme machinery in to replicate DNA sequence so covalently binding two strands interfere w ability of the cell to replicate DNA and can also lead to strand breakage which halts replication process

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39
Q

Bifunctional alkylating agents

A

can cause intrastrand linking and cross-linking (really strong)

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40
Q

This is particularly susceptible to the formation of covalent bond with alkylating agents

A

N7 atom of guanine

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41
Q

Cancer cells are most susceptible to alkylating agents in …

A

late G1 and S phases of the cell cycle (as entering into DNA synthesis pathways)

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42
Q

Cisplatin

A

alkylating agent

  • platinum analogue (platinum binds to nitrogen of DNA strand (on guanine); basically swaps it out
  • lead to interstrand crosslinks leading to inhibition of DNA synthesis and function
  • one nitrogen ion on cisplatin that can bind to that nitrogen molecule on guanine and lead to covalent cross-linking events b/w two guanine molecules
  • binds to other bases but at much lower affinities ; so guanine-directed really = guanine much more susceptible
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43
Q

Anti-folates

A
  • folic acid is an essential dietary factor that is converted by enzymatic reduction to FH4 cofactors
  • provide methyl groups for the synthesis of precursors of DNA and RNA (Thymine or uracil)
  • folic acid analogues interfere with FH4 metabolism thereby inhibiting DNA replication
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44
Q

Methotrexate

A
  • anti-folate
  • folic acid analogue that bind with high affinity to the active catalytic site of dihydrofolate reductase
  • effective during S phase and are most effective when cells are proliferating rapidly
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45
Q

Natural anti-cancer products

A
  • extracted from plants or bacteria with anti-cancer properties
  • include vinca alkaloids, taxanes, epipodophyllotoxins, camptothecins
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46
Q

Vinca Alkaloids

A
  • derived from the periwinkle plant (Vinca rosa)
  • inhibit tubulin polymerization
  • disrupts the assembly (polymerization) of microtubules involved in mitotic spindle apparatus (M phase); drugs interfere w ability of cell to enter or exit mitosis

** when not In mitosis = tubulin dimers
then microtubules when dividing = provide structure and direction for cell to divide and once cell is divided = microtubules need to depolymerize or broken down back into tubulin dimers which allows cell to finish its division and completely separate from one another **

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47
Q

Taxanes

A
  • derived from the Pacific yew tree (Taxus brevifolia)
  • promote microtubule assembly through high affinity binding
  • inhibits mitosis and cell division (M phase)
  • i.e. paclitaxel
  • encourages microtubules to stay as microtubules; inhibits depolymerization into tubulin dimers
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48
Q

Camptothecins

A
  • derived from the Camptotheca acuminata tree
  • DNA topoisomerases are nuclear enzymes that reduce torsional stress in supercoiled DNA (through strand breakage and resealing)
  • camptothecins bind and stabilize the normally transient DNA-topoisomerase I complex
  • although the initial cleavage action of topoisomerase is not affected, the re-ligation step is inhibited, leading to the accumulation of single-stranded breaks in DNA
  • these are S-phase specific drugs because ongoing DNA synthesis is necessary for cytotoxicity
  • not by initial cleavage .. cleavage still happens … but these drugs affect the re-ligation step
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49
Q

DNA topoisomerase

A

when replicating DNA, need to pull two strands apart so that the enzyme machinery can get in and read DNA strands to make a new strand of DNA but as you pull DNA strands apart that causes increase tension on the DNA strand further down and so the DNA topoisomerases are responsible for relieving torsional stress or increase coiling of DNA strands
- cut one strand of DNA temporarily to release tension and then they re-seal it together
whereas camptothecins = normally DNA strand being separated, topoisomerases run ahead to release tension and move as DNA strand replicates but these drugs stabilizes interaction and interfere with enzymes releasing tension

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50
Q

Antibiotics as anti-cancer treatment

A
  • products of soil microbe Streptomyces

- bind DNA through intercalation, block DNA synthesis and cell replication

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51
Q

Anthracyclines (Doxorubicin)

A
  • antibiotic as anti-cancer treatment
  • most widely used anti-cancer drug
  • 4 mechanisms of action:
    > inhibit topoisomerases
    > generate free radicals (DNA mutagenesis = push cell to accumulate sooo many DNA mutations that cell division is arrested and cell undergoes apoptosis)
    >high affinity binding to DNA
    > bind cellular membrane to alter fluidity and ion transport (leading to a reduction of the viability of the cell)
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52
Q

Miscellaneous anti-cancer drugs

A

used for very specific cancers in which particular mechanisms that have been identified are important

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53
Q

Tyrosine kinase inhibitors

A
  • miscellaneous anti-cancer drug
  • imantinib
  • inhibits the tyrosine kinase domain of the Bcr-Abl oncoprotein
  • treats leukemia
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54
Q

Epidermal growth factor receptor (EGFR) inhibitors

A
  • miscellaneous anti-cancer drug
  • EGFR is over-expressed in a number of solid tumours
  • activation of EGFR promotes cell growth and proliferation, invasion, and metastasis, and angiogenesis
  • Cetuximab is a monoclonal antibody directed against the extracellular domain of EGFR
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55
Q

Hormonal anti-cancer agents

A
  • miscellaneous anti-cancer drug
  • Tamoxifen
  • selective estrogen receptor antagonist
  • ## blocks binding of estrogen to estrogen sensitive cancer cells in breast tissue
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56
Q

fuels the growth and division of breast cancer cells

A

Oestrogen

  • certain breast cancers are susceptible or respond to estrogen
  • estrogen leads to or promotes cell division and many breast cancer tumours express the estrogen receptors at high levels
  • Tamoxifen inhibit estrogen signalling that can promote cell division
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57
Q

Primary Resistance

A

develops spontaneous in the absence of prior exposure to anti-cancer drugs (i.e. p53 mutations)

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58
Q

Acquired Resistance

A

develops in response to a given anticancer agent
- bc cells are rapidly dividing and acquiring more and more mutations, there’s lots of chance or opportunity for cancer cells to acquire mutations that confer some sort of resistance to the anti-cancer drug

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59
Q

Adverse effects of Anti-cancer drugs

A
  • dose related; very narrow therapeutic window = also targeting non-cancer cell mechanisms
  • occur primarily in rapidly growing tissues, such as bone marrow, intestinal mucosa, and reproductive system
  • symptoms include impaired immune system, diarrhea, hair loss, nausea, and vomiting
  • many anti-cancer drugs are carcinogenic in nature, thus increased risk of secondary malignancies
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60
Q

Adrenal Gland - Medulla

A
  • adrenaline

- catecholamine/amino acid hormone

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61
Q

Adrenal Gland - Cortex

A
  • zona glomerulosa
  • zona fasciculata
  • zona reticularis
  • steroid hormones (where corticosteroids are formed; derived from cholesterol; lipid-permeable)
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62
Q

‘HPA’ axis

A

controls cortisol release from the zona fasciculata

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63
Q

This stimulates steroid production

A

ACTH (pituitary)

  • after meals
  • circadian rhythm (high just before waking)
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64
Q

ACTH is controlled by ___ from the hypothalamus

A

CRH/CRF (corticotropin releasing factor)

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65
Q

T or F. Steroid hormones are stored like peptides

A

F! they can’t; ACTH stimulates cortisol synthesis

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66
Q

HPA axis

A

hypothalamic–pituitary–adrenal axis

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67
Q

Cortisol exerts negative feedback on:

A
  • CRH (hypothalamus
  • ACTH (anterior pituitary)
    cortisol suppresses stress signals like cytokines involved in the stress response (‘other regulatory signals’)
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68
Q

Aldosterone

A

primary target is kidneys, promotes Na+/water reabsorption, K+ excretion
- mineralocorticoid response

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69
Q

Primary role of RAAS

A

to control blood pressure/volume

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70
Q

released by the juxtaglomerular apparatus (kidney); generates AT1 from angiotensin

A

Renin

  • ACE converts AT1 to AT2
  • AT2 triggers aldosterone release
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71
Q

Many glucocorticoid target tissues () express this:

A
  • adipose, muscle, liver
  • 11beta-hydroxysteroid dehydrogenase, type 1 = activates cortisol (HSD-1)
  • corticosteroid specificity arises from affinity of the compound/receptor, AND metabolism in target tissues
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72
Q

Corticosteroid action/administration

A

Example: topical availability of Prednisone vs Prednisolone

Prednisone:

  • not very effective topically
  • widely used (oral, intake, injection)
  • must be metabolized to prednisolone to become effective

Prednisolone:

  • strong topical effect
  • active form of prednisone

**first-pass metabolism in liver and in important GC target tissues **

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73
Q

Cortisol activates the GR and MR but has weak mineralocorticoid effects in vivo. Why??

A
  • kidney cells (mineralocorticoid targets), express an enzyme (HSD-2) that renders cortisol inactive
  • HSD-2 catalyzes reverse rxn where it converts cortisol to its inactive form; prevents cortisol from inappropriately activating mineralocorticoid receptors in kidneys
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74
Q

If HSD-2 were deficient or inhibited, what consequences would you expect? How would this affect the target tissues targeted by glucocorticoids, and the spectrum of glucocorticoid effects?

A
  • Licorice contains an inhibitor of HSD-2
  • allows glucocorticoids to have an inappropriate effect in aldosterone target tissues like the kidney
  • licorice overdose = can cause high blood pressure (due to aldosterone-like effects including Na+ and water reabsorption)
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75
Q

Pseudohyperaldosteronism

A

a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA)

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76
Q

Apparent Mineralocorticoid Excess

A
  • genetic disease

- arising from mutations in the 11beta-hydroxysteroid dehydrogenase type 2 gene

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77
Q

Key glucocorticoid-mediated mechanisms in inflammation

A
  • inhibits arachidonic acid generation
  • inhibits prostanoid synthesis
    ^ these two effects have widespread downstream effects on inflammatory reactions
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78
Q

An important target for glucocorticoid action is COX-2

A
  • COX-2 is an important inflammatory mediator, early in the process of inflammation
  • COX-2 plays an early step in the metabolism of arachidonic acid to various prostanoids (depending on cell type)
  • glucocorticoid regulation of COX-2 does not involve direct receptor antagonism
  • Glucocorticoids suppress transcription of COX-2 gene, leading to a long-term suppression of COX-2 expression (protein levels)
  • they do not directly bind to cyclooxygenase activity
  • by taking corticoids, ending up suppressing component of our inflammatory response
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79
Q

Liportin induction by glucocorticoids

A
  • lipocortin/annexins are a large family of proteins characterized by ‘annexin repeats’
  • Annexin A-I plays an important anti-inflammatory role for two important reasons:
    1. direct effects on leukocytes inhibits their tissue infiltration
    2. suppression of phospholipase A2 activity; this prevents AA generation, and thereby suppresses downstream generation of prostanoids
  • these effects are very early in the inflammatory response, so they have broad powerful anti-inflammatory effects
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80
Q

Addison’s Disease

A
  • chronic adrenocortical insufficiency (fatigue, salt balance, sugar balance problems, skin discoloration)
  • low production of glucocorticoids, and often mineralocorticoids
  • typically treated with GC/MC supplementation (hydrocortisone)
    ^ supplement patients w synthetic glucocorticoids or mineralocorticoids or possible synthetic corticosteroids that have effects on both receptor types
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81
Q

Cushing’s Syndrome

A
  • adrenal overactivity leading to excessive cortisol
    > adrenal tumor (cortisol producing)
    > pituitary tumor (ACTH production, stimulation of adrenal cortex)
    > drug-induced (long course of GC treatment)
    > ectopic tumor (ACTH producing)
  • round face, fat deposition in trunk
  • muscle loss, osteoporosis - protein and bone catabolism
  • resection of adrenals or pituitary tumor, followed by gradual adjustment towards a maintenance dose of cortisol
82
Q

Glucocorticoids as therapeutics

A
  • powerful anti-inflammatory, immunosuppressive actions of cortisol and analogs
  • allergic reactions (bee stings, contact dermatitis)
  • eye inflammation (uveitis, conjunctivitis)
  • reduction of pain and scarring after injury/surgery, by reducing inflammation
  • gastrointestinal diseases (inflammatory bowel syndrome)
  • hematologic disorders (leukemia, myeloma)
  • asthma
  • organ transplants (immunosuppression to avoid rejection)
83
Q

Glucocorticoids side effects

A
  • addison-like symptoms if stopped abruptly
    > negative feedback from glucocorticoid administration will suppress CRH and ACTH production
    > ‘Addisonian’ crisis: hypoglycemia, hyponatremia, hyperkalemia, low blood pressure
    > tapering is needed when stopping long-term course of glucocorticoids (i.e. you should not abruptly stop taking a glucocorticoid; gradually reduce dose
84
Q

When you stop taking glucocorticoids meds suddenly

A

cortisol drop to low level = takes a awhile for body to re-establish its ability to synthesize ACTH, CRH, and its own cortisol
long-lived efect bc steroid hormone

85
Q

Immunosuppressive drugs are used for three main applications:

A
  1. suppression of rejection of transplanted organs and tissues
  2. suppression of graft-vs-host disease (GVHD) which may arise from donor lymphocytes reacting against host, especially in bone marrow transplants
  3. autoimmune diseases - examples include lupus (systemic lupus erythematosus), rheumatoid arthritis, psoriasis, ulcerative colitis, idiopathic thrombocytopenic purpura
86
Q

Rheumatoid arthritis

A

autoimmune disease primarily affecting the joints (but other tissues also)
- often in the elderly

87
Q

Lupus

A

multiorgan autoimmune disease (characteristic rash on cheeks - butterfly-shaped, but again many tissues are affected)

88
Q

T-cell infiltration (autoimmune) and ulceration in the colon

A

Ulcerative colitis

89
Q

Psoriasis

A

autoimmune disease leading to scaly patches of skin

90
Q

T or F. There is a lot of overlap between cancer chemotherapeutic drugs and immunosuppressants

A

T!

91
Q

IL-2

A

released and produce positive feedback on Th precursor cells that causes them to divide and diff into Th zero cells

92
Q

IL-4

A

released and exerts positive feedback of Th zero cells which causes them to divide and differentiate into either Th1 or Th2 cells and they continue to divide into Th2 -> B cells = Abs producing and Th2 -> effector cells to release cytokines

93
Q

Induction phase (of immune response)

A

includes recognition and presentation of foreign antigen, activation and proliferation of naive Th0 cells into Th1 and Th2 cells
- most of drug effects we will talk about

94
Q

Effector phase (of immune response)

A

includes cell-mediated T-cell responses (cells ‘killing’ infected or foreign cells) derived from Th1 cells, and antibody-mediated responses derived from Th2 cells (leading to activation of B cells)

95
Q

Several critical steps/regulators are targeted by available immunosuppressant drugs

A
  1. inhibition of IL-2 production/action (inhibiting positive feedback)
  2. inhibition of cytokine gene expression (glucocorticoids)
  3. cytotoxicity (killing immune cells or preventing their maturation/expansion)
  4. inhibition of nucleic acid synthesis
  5. blockage of various T-cell surface receptors to prevent immune activation (e.g. antigen presentation machinery)
96
Q

Calcineurin inhibitors

A
  • cyclosporine, tacrolimus
  • activation of naive Th0-cells, and clonal expansion of T cells requires activation of several signalling pathways including the calcineurin-NFAT (nuclear factor of activated T-cells) pathway
  • activation of the T-cell receptor generates a Ca2+ signal, leading to activation of calcineurin (phosphatase), and dephosphorylation of NFAT
  • dephosphorylated NFAT migrates to the nucleus, leading o expression of IL-2 that is required for activation and proliferation of T-cells
  • cyclosporine and tacrolimus bind to their targets (cyclophilin, FKBP, respectively); these drug-bound targets suppress calcineurin - this suppresses the pathway that leads to IL-2 gene transcription
97
Q

Cyclosporine

A

binds to cyclophilin and when bound, that complex will inhibit effect of calcineurin and that prevents dephosphorylation and all downstream effects so NFAT stays phosphorylated and thus does not migrate to nucleus and no release of IL-2 = inhibition of T-cell maturation and proliferation

98
Q

Tacrolimus

A
  • inhibition of calcineurin by the FKBP:tacrolimus complex
  • similar to cyclosporine, this prevents NFAT-mediated gene transcription, especially important is the suppression of IL-2
99
Q

Proliferation Signal Inhibitors

A
  • rapamycin, AKA sirolimus
  • these drugs interfere with the downstream signals of IL-2 receptor activation
  • rapamycin binds to FKBP (same target as tacrolimus)
  • HOWEVER, rapamycin-FKBP complex does not inhibit calcineurin, it inhibits a protein called mTOR (mammalian target of rapamycin)
  • mTOR is a major pathway responsible for promoting cell growth and proliferation
100
Q

mTOR

A

major pathway responsible for promoting cell growth and proliferation

101
Q

Rapamycin mechanism of action

A
  • inhibition of mTOR by the FKBP:sirolimus complex
  • these effects suppress cellular responses to IL-2 receptor activation
  • mTOR normally activator of cell growth but when it’s bound to sirolimus FKBP compound it’s going to act as a suppressor of pathway
102
Q

Cytotoxic agents

A
  • cyclophosphamide (alkylating agent)
  • leads to cross-linking of neighbouring bases; this interferes with DNA replication
  • most effective in rapidly dividing cells (Th cells undergoing clonal expansion), so these drugs are useful in cancer treatment, and for suppression of rapidly dividing immune cells
  • a lot less specificity = ‘dirty drugs’; interfere with cell division or DNA rep
  • bi-functional alkylating agent = each of these groups is able to react w a base in the DNA double helix; react with a neighbouring base on DNA and form crosslink; interfere ability of DNA to replicate then interfere with cell division bc unable to properly replicate genome
103
Q

Azathioprine

A
  • cytotoxic agent
  • azathioprine is metabolized to 6-mercaptopurine, a ‘fraudulent’ nucleotide (mimics head group of a purine nucleotide); this inhibits synthesis of nucleotides and interferes with cell division (effective against rapidly dividing cells during clonal expansion)
  • prevents the appropriate synthesis of purine nucleotides and that prevents cells from being able to replicate their genome and prevents them from dividing
104
Q

Antibody-based therapies

A
  • Abs always raised in other animals (monoclonal raised in mice); using these causes a problem bc they are recognized by our immune system and rapidly degraded
  • the solution is to use ‘chimeric’ or ‘humanized’ versions of murine (mouse) monoclonal antibodies; reduces their antigenicity and increases their lifetime in the body
  • have names that end with ‘mab’
    > “-umab” or “-zumab” for humanized antibodies
    > “-imab” or “-ximab” for chimeric products
105
Q

Humanization/chimerization

A

replacement of conserved regions of the mouse monoclonal antibody with corresponding sequence from human antibodies
- alter mouse sequence so part of them are human and just variable region that recognizes Ag that is retained

106
Q

Alemtuzumab

A
  • humanized IgG1 that recognizes CD52 found on many immune cell types
  • the IgG1 Fc domain is recognized by phagocytic immune cells (eg: macrophages, neutrophils, dendritic cells), complement, and NK cells … leads to cell death by lysis or phagocytosis
  • healthy and destructive T and B cells are destroyed
107
Q

Basiliximab

A
  • chimeric mouse-human IgG1 that binds to CD25, part of the IL-2 receptor (alpha chain) on activated lymphocytes
  • causes immunosuppression by blocking IL-2 from binding to activated lymphocytes (IL-2 antagonist); blocks + feedback mechanism
  • same Fc IgG1 for alemtuzumab so going to promote binding and destruction of cells based on phagocytic or lytic response by natural killer cells and so on based on recognition of Fc domain of IgG1 domain
108
Q

Bone is the principal reservoir for these ions

A

~98% of Ca2+
~85% of PO4 3-
remainder = intracellular fluid, circulation

109
Q

Why is there regulation of calcium and phosphate important?

A
  • health/strength of bones - osteoporosis, osteopenia, osteopetrosis - (long-term, chronic effects)
  • Ca2+ balance has significant effects on electrical excitability of cells, by binding to membrane glycoproteins (can lead to acute crises when Ca2+ levels are abnormal)
  • Ca2+ is an essential intracellular signal that can regulate expression of many genes
110
Q

Osteopenia

A

reduced bone density but not as extreme as osteoporosis

111
Q

Osteopetrosis

A

more dense than normal = susceptible to fractures as well; rare and severe disease

lose density = osteoporosis; easier to fracture

112
Q

Osteoblasts vs. Osteoclasts

A
  • Osteoblasts: deposition of bone
  • Osteoclasts: resorption of bone

activation of osteoclasts is indirect – the hormones activate osteoblasts; secretion of RANK ligand (RANKL) for osteoblasts activates osteoclasts

113
Q

Major regulators of bone remodeling are…

A

vit D metabolites and PTH (stimulate bone resorption)

114
Q

T or F. Resorption and deposition of bone is always happening = dynamic

A

T!

115
Q

Mechanism of RANKL

A

acts on pre-osteoclasts (cells from myeloid lineage that are differentiating to osteoclasts) = promote differentiation to a mature osteoclasts where can start break down bone = making space for osteoblasts to move into and deposit bone again; signal, hormones stimulate the osteoblasts! They don’t directly regulate osteoclasts; osteoblasts then release RANK ligand so it can bind to receptors on osteoclasts

116
Q

Secondary regulators of bone mineral homeostasis

A

FGF23, calcitonin, glucocorticoids, estrogens

117
Q

FGF23

A
  • anti-PTH/D3
  • inhibits phosphate uptake
  • inhibits D3 metabolism
  • inhibits PTH production
118
Q

Calcitonin

A
  • secreted from thyroid (parafollicular cells)
  • inhibits bone resorption
  • inhibits calcium and phosphate reabsorption in kidney
119
Q

Glucocorticoids (secondary regulator of bone mineral homeostasis)

A
  • prolonged administration causes osteoporosis (common)

- blocks calcium uptake in gut, promotes excretion in kidney

120
Q

Common in post-menopausal women due to low circulating estrogen => resorption more predominant

A

Osteoporosis

121
Q

Estrogens

A
  • prevent bone loss in postmenopausal women

- direct effects in bone, prevents PTH-stimulated resorption

122
Q

Disruptions of Ca2+ homeostasis

A
  • acute disruptions can be severe and often need to be resolved quickly - short term
  • however, there are typically underlying defects that are a long term problem and need resolution = hypocalcemia
123
Q

Hypocalcemia

A
  • short term resolution: calcium (oral, IV, IM), or active D3 metabolite
  • causes hyperexcitability of cells - early symptom is Trousseau’s sign; unresolved hypocalcemia can lead to seizures, muscle tetany/spasms
  • hypocalcemia is a side effect of having their thyroid gland (And ultimately parathyroid glands) removed; circulating amounts of PTH dropped to 0 = low circulating Ca = Trousseau’s sign
124
Q

Long-term danger is development of secondary hyperparathyroidism …

A
  • hypocalcemia
  • hyperactive parathyroid (constantly making PTH) due to low plasma Ca2+ (normally resulting from kidney failure and poor renal reabsorption of Ca2+)
  • secondary hyperthyroidism will lead to breakdown and weakening of bones
125
Q

Intrinsic defect of parathyroid, treated with vitamin D supplementation, Ca2+ supplementation

A

Hypoparathyroidism

126
Q

Vitamin D deficiency

A

inability to generate vit D metabolites, resolve by dietary correction, ingestion of active vit D3 metabolites (calcitriol), sunshine

127
Q

Hypercalcemia

A

effects related to loss of cellular excitability: lethargy, coma, also pain in bones if due to excessive PTH

128
Q

Long term hypercalcemia

A
  • defect is normally primary hyperparathyroidism
  • overactivity of the parathyroid - typically due to tumor
  • therapy is resection of the gland
  • therapeutics might be used to ‘protect bone’ (bisphosphonates, calcitonin, inhibitors of bone resorption)
  • second possible therapy is calcimimetics (mimic calcium effects on CaR, negative feedback regulation of parathyroid)
129
Q

T or F. Osteoporosis is most familiar in aging females

A

T!

  • commonly treated by hormone replacement (serious adverse effects … cancers)
  • development of estrogen mimics (SERMs, eg. raloxifene)
130
Q

Other common causes of osteoporosis

A
  • long-term glucocorticoid administration

- hyperparathyroidism

131
Q

Teriparatide

A
  • recombinant, fully active PTH fragment (1-34)
  • counterintuitive? doesn’t PTH increase circulating Ca2+ by resorbing bone?
  • PTH acts primarily as a stimulus on osteoblasts, and acts via RANKL to activate osteoclasts
  • mechanism of action requires proper timing of dosage (once daily; pulsatile manner is key!), thought to ‘tip balance’ towards osteoblast activity
132
Q

Acts on PTH receptors on the osteoblasts and triggering them to stimulate osteoclast action

A

Teriparatide

133
Q

Why is delivering teriparatide in a pulsatile manner important?

A

only given for a brief period of time so not applied long enough to allow long-term stimulation of osteoclasts ; so this pulsatile manner = stimulate osteoblast ; promotes bone building in a way
- effect of activating osteoclasts in the short term, whereas if you continuously expose someone to teriparatide = chronic activation of osteoblasts = enhanced osteoclast differentiation and activity

134
Q

Bisphosphonates

A
  • widely used
  • mechanism of action is inhibition of osteoclast resorption of bone
  • specific target is unclear, some recent concerns about side effects (cancers, abnormal fractures)
  • speculation that these may also act to inhibit glucocorticoid effects
  • trials have combined these with teriparatide, but effects inconclusive
135
Q

Most commonly prescribed bisphosphonate

A

Alendronate

136
Q

Bisphosphonate structure

A
  • all share similar structures (two phosphonate groups)
  • phosphonate groups have a high affinity for Ca2+, so these drugs accumulate in bone
  • this targets them to osteoclasts during bone resorption, and have a variety of toxic effects on osteoclasts (promotes apoptosis?)
137
Q

Osteoprotegerin

A
  • endogenous inhibitor of RANK/RANKL system; naturally occurring ‘scavenger; of RANKL
  • by binding to RANKL, it competes with RANK
  • osteoprotegerin can prevent RANKL binding and activating osteoclasts, and this inhibits bone resorption

** RANKL more freely activates receptor and increase in activation of osteoclasts = increase bone resorption = OPG knockout = low bone density **

138
Q

Denosumab

A
  • osteoprotegerin mimetics
  • monoclonal antibody directed against RANKL
  • same mechanism as the native osteoprotegerin protein (DECOY receptor for RANKL)

** RANKL more freely activates receptor and increase in activation of osteoclasts = increase bone resorption = OPG knockout = low bone density **

139
Q

‘Butterfly’ shaped gland at the base of the neck

A

Thyroid gland

140
Q

The thyroid gland releases two main classes of hormones

A
  1. T3 (triiodothyronine - MOST ACTIVE) & T4 (thyroxine) thyroid hormones
  2. Calcitonin
141
Q

Multiple levels of hormonal control of thyroid hormone production:

A
  1. TRH (thyrotropin releasing hormone, hypothalamus)
  2. TSH (thyroid stimulating hormone, anterior pituitary)
  3. T3 and T4 exert negative feedback on both upstream glands
142
Q

TSH acts on…

A

follicular cells on thyroid gland (TSH receptor) and triggers them to secrete thyroid hormone

143
Q

Thyroid hormones are made up of 2 modified ________ molecules

A

tyrosine

  • precursor protein (thyroglobulin) is tyrosine-rich
  • the tyrosines are enzymatically iodinated (iodine atoms added to the aromatic ring), 1 or 2 iodines per tyrosine ring
  • iodinated tyrosines are enzymatically coupled (2 linked rings)
  • TSH stimulation causes this precursor protein to be endocytosed and processed, followed by release of T4 and T3 (T4 is the predominant form that is released)
144
Q

T or F. Thyroid hormone is synthesized from free tyrosine

A

F, not synthesized from free tyrosine; synthesized from tyrosine that are part of precursor proteins = thyroglobulin = many tyrosines in it!

145
Q

Thyroid hormone synthesis (apical side)

A

thyroglobulin released and tyrosine molecules will be iodinated (tyrosine side chains) through the organification step; iodinated form goes through coupling where those side chains get linked to each other so have two tyrosine side chains linked together = either T4 (4 iodines) or T3 (3 iodine’s) and will just sit on the follicular lumen until the thyroid gland receives a signal to process thyroglobulin and release thyroid hormones and that signal comes in the form of TSH = thyroglobulin will get endocytosed (step 4) and proteolytically cleaved and broken up into indiv thyroid hormone residues and those get released

146
Q

Accumulation of iodine in thyroid

A
  • the thyroid gland concentrates iodide from the bloodstream (Na+/I- cotransporter)
  • iodide is transported into the follicle lumen, and eventually added to the thyroglobulin tyrosines during the iodination step
    REMEMBER: low Na inside and high outside to drive transport of other things
147
Q

Thyroid hormone receptor

A
  • breaks the rules
  • receptor is an intracellular type receptor - acts as a transcription factor after binding of thyroid hormone
  • but T3 and T4 are not very lipid soluble and need to be taken up into cells by a transporter (many different types) in order to reach their receptors
148
Q

Mechanism of action of thyroid hormone

A
  • at rest, unbound thyroid hormone receptors can associate with response elements (TRE) and recruit co-repressors (weakens gene transcription)
  • T3 and T4 ar taken up via a transmembrane receptor, and T4 is typically de-iodinated to form T3
  • T3 binding in the nucleus causes recruitment of RXR (retinoic acid receptor) to form a heterodimer with the thyroid hormone receptor
  • recruitment of co-activators leads to enhanced transcription of target genes
149
Q

Hypothyroidism

A
  • deficient thyroid function (not enough release of thyroid hormone)
  • most common causes = iodine deficiency (dietary), autoimmunity towards thyroid (Hashimoto’s thyroiditis), congenital defect, inappropriate hormonal regulation (insufficient TSH or TRH)
150
Q

Symptoms of hypothyroidism

A 
fatigue
weight gain
hypersensitivity to cold
bradycardia 
**metabolic rate depressed**
151
Q

Primary vs. Secondary hypothyroidism

A

measurement of TSH is helpful to know whether primary or secondary

  • primary = defect in thyroid function; low T4 and T3, high TSH
  • secondary = central defect (poor function of anterior pituitary or hypothalamus); low T4 and T3, low TSH
152
Q

Hypothyroidism treatment

A

hormone replacement, most commonly with synthetic thyroxine (T4) (levothyroxine) EXTREMELY commonly prescribed

153
Q

Primary defect for secondary hypothyroidism

A

low TSH; rarer

-> so low T4 and T3

154
Q

Primary hypothyroidism

A

low generation of T3 and T4 = fail to exert neg feedback so inhibition is lacking so high TSH

155
Q

Symptoms of hyperthyroidism

A 
sleep difficulty
heat (temperature) intolerance
tachycardia
weight loss
tremor 
- heightened basal metabolic rate and state of arousal
156
Q

Overactive thyroid function (excessive production of thyroid hormone)

A

hyperthyroidism

157
Q

Most common causes of hyperthyroidism

A
  • Graves’ disease (stimulatory auto-Abs against TSH receptor, these activate the receptor leading to excess thyroid hormone release; autoimmune response to TSH)
  • hyperplasia of the thyroid leading to excess thyroid hormone release (thyroid adenoma, goiter)
158
Q

Diagnosis of hyperthyroidism

A
  • measurement of TSH helpful to determine underlying cause

- detection of anti-TSH receptor antibodies too

159
Q

Graves’ disease

A
  • cause: stimulation of thyroid by anti-TSH receptor antibodies (stimulatory)
  • features: high T4, T3; low TSH (strong neg feedback to inhibit generation of TSH), detection of anti-TSH receptor antibodies, bulging eyes, exophthalmos
160
Q

Thyroid hyperplasia

A
  • cause: thyroid adenoma, goiter

- features: high T4 and T3; low TSH

161
Q

Secondary hyperthyroidism (uncommon)

A
  • cause: central defect (excessive production of TSH by anterior pituitary)
  • features: high T4 and T3; high TSH
162
Q

These are both autoimmune diseases related to the thyroid hormone

A

Graves’ disease and Hashimoto’s thyroiditis

  • Graves’ = antibodies cause stimulation of the TSH receptor
  • Hashimoto’s = antibodies recognize other thyroid-specific proteins and lead to damage of the thyroid (there is a greater infiltration of the thyroid gland with immune cells and there is destruction of the thyroid gland leading to fibrosis, etc. ; the immune response here is leading to destruction of thyroid)
163
Q

Substance in the luminal space of follicle that’s made up of iodinated and coupled thyroglobulin primarily

A

Colloid
- under normal conditions when TSH is low = lots of colloid made but hasn’t been processed and released through follicular cells so lots of colloid sitting waiting to be processed into thyroid hormone and released whereas in the active case = colloid is less apparent bc it’s all been processed through these follicular cells and released so in the case of graves disease, these follicles kind of look like follicles you would see in the active scenario of a normal person bc these are continually being stimulated to process their colloid and release thyroid hormone bc follicular cells are being activated by the anti-thyroid stim hormone receptor antibodies (have a stimulatory effect)

164
Q

Exophthalmos

A
  • feature of Graves’ disease
  • bulging eyes
  • primarily due to autoimmune damage of muscle/fibroblasts in the eye
165
Q

Goiter in Graves’ disease

A
  • due to overactivation of thyroid tissue (by stimulatory antibodies)
  • goiter can also arise in cases of hypothyroidism (such as iodine deficiency) due to increased TSH levels
166
Q

Thioamides

A
  • hyperthyroidism treatment
  • Methimazole
  • prevent iodination and coupling steps (mediated by thyroid-peroxidase enzyme)
167
Q

These are both autoimmune diseases related to the thyroid hormone

A

Graves’ disease and Hashimoto’s thyroiditis

  • Graves’ = antibodies cause stimulation of the TSH receptor
  • Hashimoto’s = antibodies recognize other thyroid-specific proteins and lead to damage of the thyroid (there is a greater infiltration of the thyroid gland with immune cells and there is destruction of the thyroid gland leading to fibrosis, etc. ; the immune response here is leading to destruction of thyroid)
168
Q

Substance in the luminal space of follicle that’s made up of iodinated and coupled thyroglobulin primarily

A

Colloid
- under normal conditions when TSH is low = lots of colloid made but hasn’t been processed and released through follicular cells so lots of colloid sitting waiting to be processed into thyroid hormone and released whereas in the active case = colloid is less apparent bc it’s all been processed through these follicular cells and released so in the case of graves disease, these follicles kind of look like follicles you would see in the active scenario of a normal person bc these are continually being stimulated to process their colloid and release thyroid hormone bc follicular cells are being activated by the anti-thyroid stim hormone receptor antibodies (have a stimulatory effect)

169
Q

Exophthalmos

A
  • feature of Graves’ disease
  • bulging eyes
  • primarily due to autoimmune damage of muscle/fibroblasts in the eye
170
Q

Goiter in Graves’ disease

A
  • due to overactivation of thyroid tissue (by stimulatory antibodies)
  • goiter can also arise in cases of hypothyroidism (such as iodine deficiency) due to increased TSH levels
171
Q

Thioamides

A
  • hyperthyroidism treatment
  • Methimazole
  • prevent iodination and coupling steps (mediated by thyroid-peroxidase enzyme)
172
Q

Antagonistic interactions

A

Drug A may act as an antagonist at a receptor for drug B

ex: effect of vitamin K on Warfarin

173
Q

Warfarin

A

anticoagulant in patients with blood clot issues (embolism, thrombosis, etc.)

174
Q

An inhibitor of vitamin K epoxide reductase

A

Warfarin

  • this enzyme recycles oxidized vitamin K (KO) to reduced vitamin K2 (KH2)
  • in the absence of cofactor (the reduced form) = the conversion to prothrombin can’t happen and so reduce ability for blood to clot
175
Q

Clotting is closely monitored by this

A

Prothrombin time (PT)

  • measure of the time required for blood to clot under a set of standard lab conditions
  • PT reported as the INR; this is the ratio of clotting time compared to a control ‘normal’ sample
176
Q

high INR

A

sample requires a long time to form a clot

177
Q

What can diminish vitamin K?

A

antibiotics may inhibit vit K production in the gut = stronger Warfarin effectiveness

178
Q

Synergism or additive interactions

A

multiple agonists/ modulators may act on the same receptor leading to excessive activation
- ex: use of benzodiazepines, alcohol, barbiturates and other modulators of GABAA receptors

179
Q

Usually refers to effects that are greater than the individual effects of two drugs

A

Synergism

180
Q

Additive interactions

A

usually refers to effects that are roughly the sum of the individual effects of two drugs

181
Q

GABAA receptor

A

Cl channel

- multiple drugs can act on it and enhance its activity

182
Q

Benzodiazepines

A
  • Xanax, Valium

- + allosteric modulators of GABAA

183
Q

PAMs or agonists of GABAA

A

barbiturates

184
Q

Alcohol

A

PAM of GABAA

185
Q

Zolpidem

A
  • Ambien

- PAM of GABAA

186
Q

Indirect interactions

A

the effects of multiple drugs might influence the same signalling pathway, but not necessarily the same receptor

187
Q

Serotonin syndrome

A
  • classic example of indirect interactions
  • arises from combinations of drugs that lead to overabundance of 5-HT/serotonin in the CNS, and overstimulation of 5-HT receptors (esp. 5-HT2A and 1A)
188
Q

Serotonin syndrome is characterized by …

A

high body temperature, agitation, sweating, dilated pupils, muscle twitching, elevated blood pressure

189
Q

Monoamine oxidase inhibitors

A
  • prevents breakdown of 5-HT/serotonin by MAO-A
  • leads to increased cellular levels of 5-HT
  • many of these act irreversibly, so they can have very long lasting effects that will increase susceptibility by serotonin syndrome when taking some of these other drugs
190
Q

Tricyclic antidepressants, SSRIs, and SNRIs

A

prevent reuptake of 5-HT from the synaptic cleft, prolonging the lifetime of 5-HT in the synapse

191
Q

Various opioids that contribute to the serotonin syndrome

A

metabolites may have direct serotonergic effects or interfere with serotonin reuptake

192
Q

St. John’s Wort

A

likely acts as a serotonin reuptake inhibitor

193
Q

MDMA, methamphetamine

A

promote serotonin release (often by causing ‘uptake’ transporters/pumps to operate in reverse

194
Q

Precursors of serotonin

A

5-HTP, L-tryptophan

- used as antidepressants

195
Q

Pharmacokinetic interactions alter drug availability

A
  1. drugs that alter gut motility, pH (antacids), can alter the absorption of a drug
  2. drugs that alter local blood flow can alter absorption of a drug (co-administration of lidocaine with epinephrine for local vasoconstriction)
196
Q

Pharmacokinetic interactions: Metabolism

A

many drugs/food can either:

  1. induce expression of specific CYP enzymes - this will reduce the lifetime and abundance of their substrates
  2. inhibit CYP enzyme activity - this will prolong the lifetime and activity of their substrates
197
Q

Most common enzyme for biotransformation of drugs

A

CYP3A4

198
Q

CYP3A4 expression is induced/enhanced by many factors:

A
  • rifampicin (antibiotic)
  • anticonvulsants (phenytoin, carbamazepine)
  • glucocorticoids
199
Q

This metabolizes (breaks down) warfarin

A

CYP3A4
- leads to an important interaction that affects warfarin response (individuals taking another drug that induces CYP3A4 will be resistant to warfarin)

200
Q

Low INR

A

more prone to clotting

201
Q

The most widely appreciated example of drug/food that can inhibit CYP enzymes

A

grapefruit juice

  • a regular grapefruit eater/drinker will have heightened sensitivity to warfarin or other drugs that are metabolized by CYP3A4
  • many drugs are broken down by this enzyme

PMCOL 200 (4 decks)

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